Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors

Abstract: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with a median survival of approximately 15 months. Standard care for GBM has remained the same for more than 10 years and has yet to produce remission. Phosphatase and tensin homolog (PTEN) is a common biomarker of GBM, whose mutation is associated with defects in homologous recombination (HR), making it a candidate for targeted therapy by synthetic lethality (SL). PARylation is a transient, post-translational modification that modulates DNA repair fidelity and genomic stability. Inhibitors of PARylation (PARP inhibitors, PARPi; PARG inhibitors, PARGi) have been developed for therapeutic use in HR-defective cancers, and their efficacy has been demonstrated in HR-deficient breast and ovarian cancers based on the concept of SL. My main goal was to identify the DNA double-strand break repair pathways activated and/or inhibited by PARPi and PARGi in function of PTEN status, and to support the concept of SL in GBM cell lines. This was accomplished by various methods including flow cytometry and immunofluorescence. Subsequently, by western blot and immunohistochemistry, I aimed to uncover the expression and localization of PARP-1 and PARG in human tissue to validate the potential of PARPi and PARGi as therapeutic agents. I revealed that inhibitor treatment caused the accumulation of GBM cells in G2 phase without the initiation of apoptosis or necrosis. Importantly, PTEN-wildtype cells displayed higher levels of DNA damage after PARPi treatment compared to PTEN-mutant cells. However, there was no indication of efficient DNA repair by NHEJ. These findings strengthen the case for PARP and PARG inhibition as inducers of DNA damage, but do not support the concept of SL between PARP inhibition and PTEN mutations in GBM cells, despite PARP-1 and PARG over-expression in GBM tissues. Further research must be done to understand the complex relationship between PARylation and PTEN, and to propose PARPi and/or PARGi for personalized therapeutic use in GBM patients

Letter, ca. 1932, Paris, to Miss Earhart

Letter, Henre Lau[rich] to Amelia Earhart, regarding Earhart's recent flight, ca. 193

Synthesis and Structural Characterization of Non-Homoleptic Carbamato Complexes of VV and WVI and Their Facile Implantation onto Silica Surfaces

The vanadium(V) amido‐carbamato derivatives VO(NR2)(O2CNR2)2 (R = Me, 1; Et, 2) are obtained by the reaction of VOCl3 with preformed carbamato species (ammonium or sodium carbamates). The synthesis of an ionic ammonium chlorido‐amide of WVI, 3, is performed using WOCl4 and diethylamine as precursors. Moreover, the reactivity of 3 with CO2 is investigated. Mixed WVI chlorido‐carbamato compounds, 4 and 5, are obtained by the reaction of WOCl4 with stoichiometric amounts of sodium diethylcarbamate. All of the products are characterized by analytical and spectroscopic methods (IR spectroscopy, multinuclear NMR spectroscopy) and by X‐ray diffraction in the cases of 3 and 4. DFT calculations are useful to elucidate the structures of the compounds and to give insight into the various reaction pathways. The combination of 2 or 5 with amorphous silica gives solid materials, which are characterized by inductively coupled plasma‐optical emission spectroscopy (ICP‐OES) and energy dispersive X‐ray spectroscopy (EDS) coupled to scanning electron microscopy (SEM)